The advent of nanotechnology holds the promise of new modalities for the treatment of disease in man. In particular, the multifunctional nature of nanoplatforms is well-suited for complex diseases that involve several different cellular compartments, such as cancer. The overall objective of project 6 is to develop and test programmable, or "smart" nanoplatforms (SNaPs) that are based on common nanoplatform cores. Nanoplatforms have been designed which will undergo spontaneous self-assembly, based on hostguest chemical interactions. The assembly is dependent upon integration of polyethyleneglycol polymer (PEG)-conjugated molecular guests, where the distal terminus of the PEG polymer can be conjugated to "programmable" elements. This host-guest based nanoplatform provides several advantages over our existing platforms: the poor pharmacological properties associated with many potent drugs are actually exploited in this approach, with fewer expected side effects, the design is highly flexible, accommodating multiple therapeutic, imaging, targeting or other effector functions within each nanoplatform, and the nanoplatforms are easily and rapidly programmable by-simple coincubation of the host and guest moieties. The capacity to incorporate multiple targeting elements into the SNaPs will be used to evaluate whether low affinity/high avidity modes of targeting represent an improvement in target cognition over current high affinity/low avidity approaches. We hypothesize that moderate-to-low affinity, high-avidity dependent interactions offer increased opportunities for true "recognition" of the platform target, particularly if heterogenous recognition of several different "sensor-ligands" is required. Finally, we will test the capacity of the programmable nanoplatform to target distinct cell populations that contribute to tumor growth and malignancy, including both vascular and tumor elements, using syngeneic and transgenic models of disease. A focus of these investigations will be the efficacy of the nanoplatform, when used to eradicate residual and metastatic disease, after ablation of the primary tumor. The capacity for SNaPs to hunt and kill residual disease is a potential strength of the nanoplatform, as recurring and metastatic disease accounts for the majority of disease morbidity. These studies will lay the groundwork for a new generation of easily programmed, multifunctional nanoplatforms, amenable to the treatment of malignancy in human patients.